Polygenic scores for psychiatric traits mediate the impact of multigenerational history for depression on offspring psychopathology

A family history of depression is a well-documented risk factor for offspring psychopathology. However, the genetic mechanisms underlying the intergenerational transmission of depression remain unclear. We used genetic, family history, and diagnostic data from 11,875 9–10 year-old children from the Adolescent Brain Cognitive Development study. We estimated and investigated the children’s polygenic scores (PGSs) for 30 distinct traits and their association with a family history of depression (including grandparents and parents) and the children’s overall psychopathology through logistic regression analyses. We assessed the role of polygenic risk for psychiatric disorders in mediating the transmission of depression from one generation to the next. Among 11,875 multi-ancestry children, 8,111 participants had matching phenotypic and genotypic data (3,832 female [47.2%]; mean (SD) age, 9.5 (0.5) years), including 6,151 [71.4%] of European ancestry). Greater PGSs for depression (estimate = 0.129, 95% CI = 0.070–0.187) and bipolar disorder (estimate = 0.109, 95% CI = 0.051–0.168) were significantly associated with higher family history of depression (Bonferroni-corrected P < .05). Depression PGS was the only PGS that significantly associated with both family risk and offspring’s psychopathology, and robustly mediated the impact of family history of depression on several youth psychopathologies including anxiety disorders, suicidal ideation, and any psychiatric disorder (proportions mediated 1.39%–5.87% of the total effect on psychopathology; FDR-corrected P < .05). These findings suggest that increased polygenic risk for depression partially mediates the associations between family risk for depression and offspring psychopathology, showing a genetic basis for intergenerational transmission of depression. Future approaches that combine assessments of family risk with polygenic profiles may offer a more accurate method for identifying children at elevated risk.


Introduction
Depression runs in families, often manifesting in various forms of mental disorders.Parental depression increases the offspring's risk of developing depression and other psychopathology, such as anxiety, disruptive disorders and substance use, by 2-5 times [1][2][3].Children with a family history of depression often develop the disorder at a younger age, even in childhood [3].Although the familial transmission of depression is established, the intricate mechanisms through which genetic predispositions and environmental factors contribute to the intergenerational transmission of depression and related psychopathologies are not yet fully understood [4,5].
Offspring with both a parent and at least one grandparent with depression are at an even higher risk for developing psychopathology [6,7].We rst found this using a longitudinal three-generational study, which used carefully crafted interview-based diagnoses for every family member, from children to adults [7][8][9] (Warner, Weissman et al., 1999), and these ndings were con rmed by other moderate sized studies [10,11].We recently generalized these ndings to a large, diverse cohort of preadolescents in the Adolescent Brain and Cognitive Development (ABCD) study.This study showed a signi cant association between family history of depression and offspring's risk of psychopathology regardless of sociodemographic characteristics such as sex, socioeconomic status (SES), and race/ethnicity [6].
Psychiatric disorders have a high degree of heritability, estimated for depression around 30-50% [12] and up to 80% for schizophrenia [13,14].These numbers came initially from twin studies [15], which cannot readily distinguish between genetic and intrauterine and perinatal factors or differences between parenting monozygotic versus dizygotic twins.Recent adoption studies, which found a larger component attributed to being reared by a depressed (step/adoptive) parent, questioned whether the genetic component of intergenerational depression was overestimated in these early twin studies [16,17].A recent large-scale registry study, however, con rmed the initial heritability estimates [18].These studies suggest a strong role for genetics in the transmission of depression between generations.Nonetheless, the variance explained by genetic components is not attributed to a few candidate genes or variants, but rather to the cumulative impact of numerous variants, each with small effects.As an example, a metaanalysis involving three independent depression genome-wide association studies (GWASs), with a total sample size of 807,553 participants, identi ed 102 genome-wide signi cant variants and 269 putative genes associated with depression [19].Polygenic scores (PGSs) represent an estimate of relative cumulative genetic risk of an individual for the phenotype of interest, such as depression, based on the ndings of GWAS.PGSs for psychiatric disorders are associated with increased risk for psychopathology in the general population [20].Some studies have jointly examined PGS and family history in association with psychopathology, but the ndings have been mixed.PGS for depression was associated with a continuous score of rst-degree (parents and siblings) family history loading for depression [21], but two other studies found no association between rst-degree family history and depression PGS [22,23], perhaps because they used the data from earlier and smaller GWASs.Furthermore, while various psychopathology PGSs were found to be associated with mood and psychotic disorder onsets, only nonpsychopathology PGSs for neuroticism and wellbeing were associated with onsets independent of family history [24].Thus, it remains unclear how family history for depression and PGSs are associated with offspring psychopathology onset.Importantly, to our best knowledge, no studies have yet reported whether family history of depression over two generations is linked to greater polygenic risk for mental disorders.
In the present study, we rst test whether multigenerational family risk for depression (having both a parent and a grandparent with depression) is independently associated with greater polygenic risk for psychiatric disorders.Then we test whether PGSs are associated with the presence of psychopathology.
We hypothesize that as more previous generations have been affected by depression, a greater genetic risk for psychopathology and related behavioral vulnerabilities would have been accumulated in the offspring, Since psychiatric disorders are genetically correlated with non-psychiatric phenotypes such as educational attainment, subjective wellbeing, and risky behaviors [25][26][27], polygenic scores for a broad array of phenotypes were used to test our research questions.Lastly, we explore whether PGSs partially mediate the association between multigenerational family risk for depression and higher rates of psychiatric diagnoses in the offspring.We test this using a mediation model that incorporates depression PGS, alongside family risk and clinical data, in the ABCD study, which has the advantage of large sample size and generalizability, making it well-suited for rigorous genetic analyses.

Participants and Data Source
This study used baseline data of 11,875 participants aged 9-10 years from the ABCD study release 2.01, collected September 2016-November 2018 [28] across 21 research sites in the United States.The genetic ancestry of children to categorize the sample was obtained from release 3.0 (https://nda.nih.gov/study.html?id=901).All procedures for data collection were approved by the centralized institutional review board (IRB) at University of California, San Diego.Caretakers provided written informed consent and children provided assent.We imputed missing values of covariates and excluded participants without genotypes, family history, and clinical outcomes.After preprocessing genotype data and validating PGSs with a validation set, 8,620 samples remained.From 8,620 genotyped samples, we excluded anyone with missing values of family history (n = 493) and KSADS-5 (n = 507).The nal sample (Fig. 1
The posterior effect sizes of single nucleotide polymorphisms (SNPs) were estimated using PRS-CSx [49], a Bayesian approach that enables the merging of multiple GWAS summary statistics from diverse populations.The nal scores were calculated using PLINK version 1.9 and controlled for the rst ten genetic principal components.The optimal hyperparameter (global shrinkage hyperparameter in PRS-CSx) for PGSs was selected in a held-out validation set of 1,579 unrelated participants.These participants were genetically related to the nal samples and therefore were excluded from the primary analyses.Details about the GWASs and validation procedures of PGSs are presented in Supplementary nor G2 (G1-/G2-; a reference level), (2) only G1 (G1+/G2-), (3) only G2 (G1-/G2+), and ( 4) both G1 and G2 (G1+/G2+).Having one parent or one grandparent was su cient to be categorized as having a parent (G2+) or grandparent (G1+) with depression.Additionally, we developed a binary "any family history" indicator to simplify the analysis.This indicator contrasts families with no reported depression history in either generation (G1-/G2-) against those with a reported history in at least one generation, so collapsing G1+/G2-, G1-/G2+, and G1+/G2 + groups into one variable "FamHist+".Furthermore, we introduced a parental history indicator (G2-vs.G2+), speci cally to highlight the impact of having a parent with a history of depression.This indicator focuses on the more immediate familial in uence, distinguishing between participants without a parental history of depression (G2-) and those with such a history (G2+).
Childhood psychopathology was assessed by the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS) [50,51] reported by parents and children.Parent and child reports were separately analyzed; therefore, a total of 36 clinical variables were included in the analyses.Further details for the measures are in the Supplementary Methods.

Potential Confounders
We used the following 13 covariates to adjust for potential confounding effects: child's age, sex, race/ethnicity, sexual orientation reported by child and parent, gender identity, religious preference, country of birth, reporter's relationship to child, total household income, and caregiver's age, education level, and marital status.Multiple imputation method using the R package 'mice' v3.14.0 was employed to impute missing values in covariates (See Supplementary Methods).

Statistical Analysis
We primarily analyzed (using R version 4.2.0.) the data of 8,111 multi-ancestry children.We repeated the analyses in 6,151 European-ancestry samples to test for ancestral bias.Bonferroni and false discovery rate (FDR) corrections for the number of tests were applied to each analysis with signi cance set at adjusted P < .05.We centered and scaled the PGSs and continuous variables of covariates to obtain standardized estimates from regression analyses.

Association and Mediation Analysis
. Association between family history of depression and PGSs was assessed using univariate linear models, with the family history indicator as the independent variable and PGS as the dependent variable.
Firth logistic regression was used when KSADS was the outcome with family risk and/or PGS as predictors including covariates [52].Firth's approach helps reduce bias in highly imbalanced data by penalizing the likelihood function.We computed 95% con dence intervals (CIs) and McFadden's pseudo R 2 with penalized log-likelihood [53].
For mediation analysis (using package 'mediation' v4.5.0), we selected the PGSs that were signi cantly associated with both clinical outcome and family history of depression and tested these as candidate mediator.The treatment variable was the familial risk of depression, considering the lowest risk (G1−/G2−) as the control condition and the others (either G1 + or G2+) as the treatment condition.
Clinical outcomes that were signi cantly associated with both PGS and family history of depression were examined as outcome.We additionally tested the models with parental risk only.Signi cance of the direct effects of familial risk and the mediation effects of PGSs were estimated using bootstrap samples (n = 1,000).

Additional Assessment/Sensitivity Analysis
Our main analyses de ned depression family history only by the depression question in the Family History Assessment.However, this does not exclude individuals who might have both depression and mania (e.g.likely bipolar disorder).Therefore, we performed a sensitivity analysis (n = 6,925 multiancestry participants, including n = 5,274 European-ancestry) removing children who have parents or grandparents with mania obtained from the Family History Assessment (Fig. 1).

Participants
The complete phenotype and genotype data from 8,111 unrelated multi-ancestry children were available for analysis, including 6,151 European-ancestry children.1A).Speci cally, children from the highest familial risk category (G1+/G2+) displayed signi cantly elevated polygenic risks compared to those from the lowest risk category (G1-/G2-).However, no signi cant differences in PGS were observed among children with a history of depression in either parents or grandparents (FamHist+), as opposed to those with the lowest familial risk (G1-/G2-).When isolating parental history regardless of grandparental history (G2-vs.G2+), children with a parental history of depression showed signi cantly higher polygenic risks for depression ( 1C).These ndings demonstrate that the effect sizes associated with multigenerational history for PGS are larger than those observed for parental history alone.Additionally, the same analyses conducted exclusively with European-ancestry children yielded results consistent with those from the multi-ancestry children (Supplementary Fig. 2).
Follow-up linear regression analyses revealed that family risk remained signi cantly associated with the PGSs for depression and bipolar disorder, after accounting for the potential confounding variables.Speci cally, children with the highest familial risk exhibited signi cantly higher polygenic risk compared to those with the lowest risk (G1-/G2-vs.3).
As a sensitivity analysis, we excluded children with family history of mania and repeated the analyses.

Association between Psychopathology and Polygenic Scores
We investigated whether the PGSs associated with family history of depression would similarly be associated with offspring's psychopathology.With the four-level family risk variable included in the models with depression PGS, PGS for depression was still signi cantly associated with KSADS diagnoses such as any psychiatric disorder, conduct/oppositional de ant disorder, conduct disorder, any anxiety disorder, sleep problems, and suicidal ideation (FDR-corrected P < .05;Supplementary Table 9).The including both depression PGS and family risk accounted for a slightly greater variance of KSADS diagnoses (parent-reported any psychiatric disorder; 2.59%) than the model including only family history of depression (2.41%).Likewise, in European-ancestry samples, depression PGS showed signi cant effects on similar KSADS diagnoses including both family history and depression PGS (FDR-corrected P < .05;Supplementary Table 10).

Mediation Analysis with as Mediators
Given that only the depression PGS was found to be signi cantly associated with both familial depression history and offspring's psychopathology, we further investigated whether depression PGS mediated the effects of familial depression history on offspring's psychopathology.
The mediation models with the binary indicator of any family history (G1-/G2-vs.FamHist+) showed that depression PGS had signi cant mediation effects on all tested  4A).The proportions mediated by depression PGS relative to the total effects on each clinical outcome ranged from 1.39-5.87%.Similar results were observed with the mediation models of parental depression history.Depression PGS had signi cant mediation effects on all 14 KSADS diagnoses, except for parent report of suicidal ideation (Fig. 4B).Likewise, in European-ancestry samples, depression PGS signi cantly mediated the impact of multigenerational and parental family risk on KSADS diagnoses (Supplementary Fig. 7).

Discussion
Familial history of depression increases risk for offspring psychiatric disorder.Therefore, we investigated whether polygenic risks for psychiatric disorders contribute to intergenerational transmission of depression.We found that multigenerational depression history was positively correlated with higher genome-wide PGSs for depression and bipolar disorder.Moreover, a greater PGS for depression signi cantly mediated the effects of familial history of depression on offspring's mental health indexed by KSADS diagnoses.To our best knowledge, this is the rst report showing polygenic risk for depression as a potential mechanism for the transgenerational transmission of depression.
Addressing con icting results from previous research on the association between rst-degree family history and depression PGS [21][22][23], the present study utilized more recent and larger GWAS results for constructing the PGS of depression, which could partially account for the discrepancies between the ndings as well as testing ndings in a larger cohort.For the rst time, our results reveal that higher depression PGS is signi cantly associated with a family history of depression spanning multiple generations, encompassing risks from both rst-and second-degree family members.The children with two previous generations affected showed the highest PGS (estimate, 0.129 [95% CI, 0.070-0.187]) in line with the increased risk for psychopathology [6].These offspring with two previous generations affected might form a subgroup of individuals with an exceptionally high genetic burden.
We found a similar association for bipolar PGS (estimate, 0.109 [95% CI, 0.051-0.168]).But when we limited the sample to those with a family history of depression without mania, bipolar PGS lost its signi cance in the association with family history.This shows that the signi cant associations with bipolar PGS might be due to including children with a family history of bipolar disorder and that genetic risk for and familial aggregation of depression and bipolar disorder are separate.This is in line with recent literature showing an association between family history of bipolar disorder and higher bipolar PGS in offspring [54][55][56], reports of familial transmission being speci c to type of mood disorder [57] and genetic differences between depression and bipolar disorder [58].
Our results also showed that depression PGS and family history of depression together accounted for signi cant variances of offspring's psychopathology.These results extend previous ndings from recent studies that showed family history and PGS are predictive of future cases of depression and including both factors in a model modestly increases the prognostic power in predicting depression [59][60][61].
The depression PGS was positively correlated with a wide range of KSADS diagnoses, including any psychiatric disorder, any anxiety disorder, suicidal ideation, ADHD, and conduct/oppositional de ant disorder (C/ODD).On the other hand, bipolar PGS showed no signi cant correlations with KSADS diagnoses.Despite not surviving correction for multiple comparisons, depression PGS was associated with any depressive disorder even at this young age of 9 to 10 years old (unadjusted P = .019).Depression often starts later in adolescence and early adulthood, but higher family and polygenic risk of depression have been shown to be associated with earlier onset [3,62].Suicidal ideation and self-harm at this age, also associated with depression PGS, are becoming more common in recent years [63] and are predictive of later suicide attempts [64].However, identifying those at risk for suicide is challenging.Our results indicate that the combination of family assessments and PGS for depression might increase predictive power in evaluating risk for suicidal thoughts and behaviors in children, especially as PGS are thought to be able to explain more variance in the future as GWASs include ever larger samples.
PGS for depression signi cantly mediates the effects of family history on offspring's depression.Moreover, the mediation effect was signi cant for a broad range of psychiatric disorders, including any psychiatric disorder, any anxiety disorder, suicidal thoughts and behaviors, C/ODD, and ADHD.This highlights a role for genetic liability in intergenerational transmission of childhood psychopathology in general and depression speci cally in periadolescent children (9-10 years old).Future research may examine the brain correlates of family history of depression and depression PGS.
Family history of depression may affect the offspring's risk for psychiatric disorders through genetic or environmental pathways.Here we show that the genetic component is signi cant and scales with the number of generations affected.On the other hand, children of parents with depression may experience and even generate more stressful life events [65, 66].These events may exacerbate risks of psychiatric disorders.Further research could identify protective or vulnerability factors that may moderate the impact of family history of depression and depression PGS through gene-environment interactions.Furthermore, because we did not have access to parent and grandparent genotypes, we are unable to distinguish between direct genetic effects of the child's genotype on their phenotype and indirect genetic effects through genetic nurture and other mechanisms.For example, the parent and the child may share a genotype associated with higher neuroticism, which could lead to less affectionate caregiving of the parent to the child [67,68].This, in turn, might bias our estimates of the direct effect of the neuroticism PGS on child psychiatric outcomes through altered parenting.

Strengths and Limitations:
The current study has the strengths of a large, diverse multi-ancestry sample, multigenerational family history assessment, and the latest Bayesian polygenic prediction method to test our hypotheses.Limitations of this study include that in most GWASs, the PGSs were derived from European-ancestry samples and, therefore, the generalizability of the summary statistics to other ancestry samples might be limited.Nevertheless, our ndings were consistent across the analyses of multi-ancestry and European-only samples.In addition, PGSs still only account for relatively small variances compared to the heritability of depression estimated from twin studies or DNA, but PGS may become stronger predictors in future.Family history was assessed retrospectively by the caregiver, which may bias reports and underestimate effect sizes compared to samples with gold-standard clinician-based diagnoses for all family members.However, this limitation is mitigated by the fact that we previously showed that clinical results were similar between an interview-based design study [7,8] and the ABCD study [6].
Lastly, the effect sizes that we found, while similar to those of prior polygenic score studies [69,70] are small, suggesting that these PGS do not yet have high clinical signi cance.As GWAS discovery samples become larger and include multiple genetic ancestries, clinical signi cance may improve.On the other hand, the children in our sample are still young and before the median age of onset of depression.Some of the currently unaffected children might develop psychiatric disorders as the cohort ages, forming a stronger association between PGS and psychiatric disorders, and increasing the effect sizes.
In summary, we show that PGSs for depression and bipolar disorder are associated with family history of depression and that depression PGS mediates part of the association between (multigenerational) family history and offspring's psychopathology.We demonstrate that having more previous generations affected with depression is linked to having higher polygenic risk for psychiatric disorders.The ndings also implicate polygenic risk for depression as a potential mechanism for intergenerational transmission of depression, suggesting that integrating depression PGS with depression history may aid in identifying children at higher risk for psychopathology.(G1−/G2+), and both G1 and G2 (G1+/G2+).Detailed information underlying this gure are available in Supplementary Table 2. (B)Regression of binary any family history: neither G1 nor G2 (G1−/G2−; reference level) and the rest of the groups (FamHist+).Detailed information underlying this gure are available in Supplementary Table 3. (C) Regression of parental depression history: no history in the parent (G2-; reference level) and depression in the parent (G2+).Detailed information underlying this gure are available in Supplementary Table 4.
Figure 3 Effects of depression PGS on clinical outcomes in multi-ancestry children a reported child; otherwise reported by parent Presented results in the gure were from the models with signi cant effects of depression PGS after the FDR correction.No signi cant result was found with bipolar disorder PGS.Error bar indicates 95% con dence interval.P values were adjusted for 72 tests (36 outcomes and 2 PGSs of depression and bipolar disorder).Detailed information underlying this gure are available in Supplementary Table 5.

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Figure 2 Effects
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Table 1 and
Supplementary Methods in Supplementary Material.Measures All assessments were reported previously in van Dijk et al. (2021) published in JAMA Psychiatry [6].The ABCD Family History Assessment was used to collect caregivers' reports on the history of grandparents (generation 1 [G1]) and parents (generation 2 [G2]) (Rice et al., 1995).We created a four-level depression risk variable, which describes risk levels of depression history from the two generations: (1) neither G1
First, we tested whether multigenerational family risk for depression is associated with greater polygenic risk.Our primary analysis included all children (a multi-ancestry sample), and our supporting analysis included only European-ancestry children to test for potential bias related to ancestry.Our analyses using linear regression without adjusting for potential confounders demonstrated a signi cant association between multigenerational family risk for depression and increased PGSs for depression (estimate, Supplementary Table5).However, bipolar disorder PGS was not associated with any clinical outcomes (unadjusted P > .05).Within the regression models, the variances explained by depression PGS ranged from 0.15-0.65%.In European-ancestry children, depression PGS was also positively associated with behavioral problems, suicidal behaviors, and any psychiatric disorder (FDR-corrected P < .05;SupplementaryFig.6; Supplementary Table6).when testing associations between family history of depression and KSADS diagnoses, we observed that the risk for psychiatric disorders and suicidal behaviors increases as family risk increases both in multi-ancestry and European-ancestry children (Supplementary Table 7-8), similar to what we have found previously [6].